We have previously established that rat and human hepatic HMG-CoA reductase activity is modulated in vitro and in vivo in a bicyclic cascade system involving reversible phosphorylation of both HMG- CoA reductase and reductase kinase. We have also demonstrated that enzymic activity of HMG-CoA reductase is also modulated in vitro by a protein kinase C-mediated phosphorylation. Recently we have demonstrated that HMG-CoA reductase activity is modulated by a third kinase system, a Ca calmodulin dependent kinase, involving covalent phosphorylation. Recently in Hep G2 cells we have also investigated the short-term (reversible phosphorylation) and long- term (decreased protein synthesis) control of HMG-CoA reductase by utilizing ligands such as LDL and 25-hydroxycholesterol. In order to understand the coordinate regulation of HMG-CoA reductase, cholesterol synthesis, and role of apolipoproteins such as apolipoprotein A-I (apoA-l) and apolipoprotein B (apoB) in the transport and regulation of cellular cholesterol, a systematic investigation of their role in plasma lipid and lipoprotein transport and metabolism has been undertaken. HDL have been proposed to transport excess cholesterol from peripheral cells back to the liver. Clinically, there is an inverse relationship between plasma apoA-I as well as HDL cholesterol levels and an increased risk of premature cardiovascular disease. During the past year we have studied the post-translational modification of human plasma apoA-I involving reversible phosphorylation. In order to establish the physiological relevance of in vitro phosphorylation of human apoA-I, we have also demonstrated that secreted and intracellular apoA-I from Hep G2 cells were phosphorylated. The phosphorylation of apoA-I may play an important role in lipoprotein assembly, intracellular transport, as well as processing and lipoprotein secretion.